1,2,4-Oxadiazole compounds as inhibitors of the CD47 signaling pathway

Abstract

To provide novel CD47 inhibitors that block SIRP1α-CD47 signaling pathway for the treatment of disorders that are mediated by the elevated levels of CD47 expression.SOLUTION: There are provided compounds represented by the following formula (I), or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof. The compounds are useful in the treatment of cancer, infectious diseases (bacterial, viral, fungal, and parasitic), atherosclerosis and multiple sclerosis. (Wherein Ra and Rb are each independently H or the like; R1, R2, and R3 are each independently H, -(CH2)2CONH2, -(CH2)3NH(C=NH)NH2, -CH2-unsubstituted aryl, -CH2-unsubstituted heteroaryl or the like; Ra and R1, together with the atoms to which they are attached form pyrrolidine ring optionally substituted with oxo group; and Rb and R3, together with the atoms to which they are attached form pyrrolidine ring.).SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of Indian Patent Provisional Application No. 201841001438, filed on January 2, 2018, the content of which is incorporated herein by reference in its entirety.

[0002] Technical Field The present invention relates to 1,2,4-oxadiazole compounds of formula (I) that are therapeutically useful as CD47 signaling pathway inhibitors. The present invention also relates to pharmaceutical compositions comprising said compounds, or pharmaceutically acceptable salts or amides or esters or stereoisomers thereof.

Background Art

[0003] Background Antagonist antibodies targeting CTLA-4, PD-1 and PD-L1 affect the adaptive immune system, mainly T cells, and have shown impressive clinical efficacy in a wide range of cancers. In subsets of patients, these T cell-based checkpoint inhibitors have been successful, but most patients still do not show a sufficient clinical response. Checkpoint proteins on cells of the innate immune system are also known to regulate the immune response. Among the innate immune checkpoint proteins, CD47 is upregulated in a wide range of malignant tumors that negatively regulate macrophage-mediated phagocytosis. CD47-mediated phagocytosis is mainly mediated by interaction with SIRP1α expressed on macrophages. Blockade of SIRP1α / CD47 dramatically enhances tumor cell phagocytosis and dendritic cell maturation for better antigen presentation, and preclinical models of cancer ​​​​​​​​​​​​​It has been shown to lead to substantially improved antitumor responses in patients with t al. Curr Opin Immunol. 2012 (2): 225-232).

[0004] CD-47 as a target for eliminating tumor cells Integrin-associated proteins (IAPs), ovarian cancer antigen OA3, Rh-associated antigens and ME CD47, also known as R6, is a transmembrane protein that is expressed in humans by the CD47 gene. CD47 is a member of the immunoglobulin superfamily and is a membrane-associated It is associated with the ligand thrombospondin-1 (TSP-1) and signaling regulator CD47 also binds signaling inhibitor protein alpha (SIRPα), which is expressed on phagocytes. phagocytic elimination of healthy cells by binding to signaling inhibitory protein alpha (SIRPα) It is best known for its pivotal role in preventing SIRPα, an inhibitory protein that inhibits phagocytosis of CD47-expressing cells, is induced. This CD47 / SIRPα axis regulates the elimination of healthy cells that express CD47. In contrast, C is an important homeostatic mechanism that prevents damage to, aging, and excess cells. Downregulation of D47 ensures their timely removal.

[0005] CD47 is expressed on virtually all non-malignant tumor cells, and blocking CD47 or CD4 Loss of expression or changes in membrane distribution are observed in aging cells, especially in red blood cells (RBCs). Blockade of SIRPα may also inhibit phagocytosis. Cells that are normally phagocytosed in which pre-phagocytic signals are also present Enable phagocytosis of non-targeted cells. CD47 is a transmembrane glycoprotein that is widely expressed and has a single Ig-like domain and five transmembrane regions, and functions as an intracellular ligand for SIRPα through binding mediated by the NH2-terminal V-like domain of SIRPα. SIRPα is mainly expressed on the surface of myeloid cells including macrophages, granulocytes, bone marrow dendritic cells (DCs), mast cells, and their precursors including hematopoietic stem cells.

[0006] CD47 is also constitutively upregulated in a number of cancers such as non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), breast cancer, colon cancer, glioblastoma, glioma, ovarian cancer, bladder cancer, and prostate cancer. Overexpression of CD47 by tumor cells efficiently assists tumor cells in evading killing by immune surveillance and innate immune cells.

[0007] It has been shown that CD47 can be considered a potential target for the treatment of atherosclerosis. This is because the process of atherogenesis, i.e., the formation of atherosclerotic plaques in the arterial wall, is associated with upregulation of CD47, which renders malignant tumor cells resistant to programmed cell death or "efferocytosis". This effect on efferocytosis is reversed by administration of CD47-blocking antibodies, which normalize the clearance of diseased vascular tissue and improve atherosclerosis in multiple mouse models (Kojima Y, et al., Nature. 2016 Aug 4; 536 (7614): 86-90). Furthermore, blockade of CD47 with a CD47-Fc fusion protein is effective in modulating experimental autoimmune encephalomyelitis (EAE), an animal model for the pathology of multiple sclerosis (MS). It has been reported that it provides potential therapeutic targets in preventing and treating MS (Gao Q et al., J Autoimmun. 2016 May; 69: 74- 85).

[0008] Compounds that modulate CD47 (i.e., antibodies and peptides) are disclosed in US20160 304609, WO2016188449, US20170081407, WO2017 194627 and WO2017194634 and a number of other publications have been published.

[0009] Despite multiple developments in recent years, there remains an unmet need for effective CD47 inhibitors that block the SIRP1α-CD47 signaling pathway for the treatment of cancers mediated by elevated levels of CD47 expression. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0010] SUMMARY OF THE INVENTION The present invention provides compounds and their pharmaceutically acceptable salts. These compounds are capable of suppressing and / or inhibiting the CD47 signaling pathway. MEANS FOR SOLVING THE PROBLEM

[0011] In one aspect, the present invention provides a compound of formula (I):

Chemical formula

[0012] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or amide or ester or stereoisomer thereof, and a process for preparing such a composition.

[0013] Yet another aspect of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof including administering an amide or ester or stereoisomer thereof, for treating a disease or disorder mediated by CD47 There is provided a method for treating a disease or disorder mediated by CD47

DETAILED DESCRIPTION OF THE INVENTION

[0014] DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1,2,4-oxadiazole compounds and their derivatives as therapeutic agents useful for treating disorders mediated by CD-47

[0015] Each embodiment is provided by the description of the present invention, but is not a limitation of the present invention. In fact, it will be apparent to those skilled in the art that various improvements and changes can be made to the compounds, compositions and methods described herein without departing from the scope and spirit of the present invention. For example, features illustrated or described as part of one embodiment can be applied to another embodiment to generate further embodiments. Accordingly, the present invention is intended to include such improvements and changes, as well as their equivalents. Other objects, features and aspects of the present invention will be disclosed in or will be apparent from the following detailed description. It should be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the present invention

[0016] In certain embodiments, the present invention provides a compound of formula (I):

CHEMICAL FORMULA

[0017] In certain other embodiments, the present invention is R a is hydrogen; and R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2C ONH2, -CH2-aryl, or -CH2-heteroaryl; or R aand R1, together with the atom to which they are attached, form a pyrrolidine ring; R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-heteroaryl ; R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2) 4NH2 or -CH2-heteroaryl; or R b and R3, together with the atom to which they are attached, form a pyrrolidine ring, to provide a compound of formula (I).

[0018] In certain embodiments, the present invention provides R a is hydrogen or acyl; and R1 represents hydrogen, -CH2COOH, -(CH 2)3NH(C=NH)NH2, -CH2CONH2, -CH(CH3)-CH2-CH 3, or -CH2-heteroaryl; wherein the aryl and heteroaryl are unsubstituted; or R a and R1, together with the atom to which they are attached, form a pyrrolidine ring substituted by an oxo group in the position ; R2 represents hydrogen, -CH2-OH or -CH2-heteroaryl; wherein the heteroaryl is unsubstituted; R b is hydrogen; R3 represents -CH2-aryl, -CH(CH3)2-CH2CO OH, -CH(CH3)-CH2-CH3, -CH2-CH(CH3)2, -(CH2) 2COOH, or -(CH2)4NH2; wherein the aryl is unsubstituted, to provide a compound of formula (I).

[0019] In certain embodiments, the present invention R a is hydrogen or acyl; R1 is -(CH2)2CONH2, -(CH2) 4NH2, -(CH2)3NH(C=NH)NH2, or -CH2-heteroaryl wherein said heteroaryl is unsubstituted; R2 is -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(C H2)2COOH or -CH2-aryl; wherein said aryl is unsubstituted; R b is hydrogen; and R3 is hydrogen, -(CH2)2CONH2, or -CH 2-heteroaryl; wherein said heteroaryl is unsubstituted; or R b and R3 together with the atom to which they are attached form a pyrrolidine ring, providing a compound of formula (I).

[0020] In certain embodiments, R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2C ONH2, -CH(CH3)-CH2-CH3, -CH2-aryl, or -CH2- heteroaryl; wherein said heteroaryl is unsubstituted.

[0021] In certain embodiments, R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2C ONH2, -CH(CH3)-CH2-CH3, -CH2-phenyl, -CH2-ind olyl or -CH2-imidazolyl.

[0022] In certain embodiments, R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2C ONH2, -CH2-phenyl, or -CH2-imidazolyl.

[0023] In certain embodiments, R1 is -(CH2)2CONH2, -(CH2)2COO H, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2CONH 2, -CH2-phenyl, or -CH2-imidazolyl.

[0024] In certain embodiments, R1 is -(CH2)2CONH2, -(CH2)2COO H, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, or -CH2- imidazolyl.

[0025] In certain embodiments, R1 is -(CH2)2CONH2, -(CH2)2COO H, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2CONH 2, or -CH2-phenyl.

[0026] In certain embodiments, R1 is -(CH2)2CONH2, -(CH2)2COO H, -(CH2)3NH(C=NH)NH2, or -(CH2)4NH2.

[0027] In certain embodiments, R1 is -(CH2)3NH(C=NH)NH2, -(CH 2)2CONH2, or -(CH2)2COOH.

[0028] In certain embodiments, R1 is -(CH2)2COOH, -CH2COOH, -C Represents H2CONH2, -CH(CH3)-CH2-CH3, or -CH2-aryl ; The aryl is unsubstituted.

[0029] In certain embodiments, R1 is -(CH2)2CONH2, or -(CH2)2 represents COOH.

[0030] In certain embodiments, R a is hydrogen. In certain embodiments, R a is a silyl. In certain embodiments, R a is acetyl.

[0031] In another embodiment, in formula (I), R a and R1 together with the atom to which they are attached form a pyrrolidine ring optionally substituted with an oxo group.

[0032] In certain embodiments, R2 is hydrogen, -CH2-OH, -(CH2)3NHC(= NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl yl, -CH2-indolyl or -CH2-imidazolyl.

[0033] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - (CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, or -CH 2-imidazolyl.

[0034] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - (CH2)2CONH2, -(CH2)2COOH, or -CH2-phenyl.

[0035] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - Represents (CH2)2COOH or -CH2-phenyl.

[0036] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - represents (CH2)2CONH2 or -(CH2)2COOH.

[0037] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - represents (CH2)2CONH2 or -(CH2)2COOH.

[0038] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - represents (CH2)2CONH2, -(CH2)2COOH, or -CH2-phenyl.

[0039] In certain embodiments, R2 is hydrogen or -(CH2)3NHC(=NH)NH 2.

[0040] In certain embodiments, R3 is hydrogen, -(CH2)3NHC(=NH)NH2, - CH2COOH, -CH(CH3)-CH2-CH3, -CH2-CH(CH3)2, - represents (CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2, -CH2- phenyl, -CH2-indolyl or -CH2-imidazolyl.

[0041] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH(CH 3)-CH2-CH3, -CH2-CH(CH3)2, -(CH2)4NH2, or - represents CH2-imidazolyl.

[0042] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH(CH 3)-CH2-CH3, -CH2-CH(CH3)2, -(CH2)4NH2, or - CH2-imidazolyl.

[0043] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2) 4NH2, or -CH2-heteroaryl; the heteroaryl is unsubstituted .

[0044] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2) 4NH2 or -CH2-imidazolyl.

[0045] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, or -(C H2)4NH2.

[0046] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, or -(CH2)2COOH.

[0047] In certain embodiments, R3 is hydrogen, -CH(CH3)-CH2-CH3, -CH 2-CH(CH3)2, -(CH2)2COOH, or -CH2-heteroaryl, representing ; the heteroaryl is unsubstituted.

[0048] In certain embodiments, R3 represents -CH2-phenyl, -(CH2)3NHC(=N H)NH2, -(CH2)2COOH, or -(CH2)4NH2.

[0049] In certain embodiments, R b and R3, together with the atom to which they are attached, form a pyrrolidine ring.

[0050] In another embodiment, the present invention provides that R a is hydrogen or acyl; and R1 is hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH 2, -CH2CONH2, -CH(CH3)-CH2-CH3, -CH2-phenyl, - CH2-indolyl, or -CH2-imidazolyl; wherein the phenyl, indol yl and imidazolyl are unsubstituted; or R a and R1, together with the atom to which they are attached form an optionally oxo-substituted pyrrolidine ring; R2 is hydrogen, -CH2-OH, -(CH2)3NHC(=NH)NH2, -(CH2 )2CONH2, -(CH2)2COOH, -CH2-phenyl, -CH2-indolyl , or -CH2-imidazolyl; wherein the imidazolyl is unsubstituted; R b is hydrogen; and R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-C H(CH3)2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4 NH2, -CH2-indolyl, or -CH2-imidazolyl; wherein the phenyl , whether indolyl and imidazolyl are unsubstituted; or R b and R3, together with the atoms to which they are attached, form a pyrrolidine ring, to provide a compound of formula (I). In certain embodiments, the present invention

[0051] is such that R a is hydrogen; and R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2C ONH2, -CH2-phenyl or -CH2-imidazolyl; or R a and R1, together with the atoms to which they are attached, form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, or -CH2-imidazolyl; R b is hydrogen; R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC( =NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4N H2, or -CH2-imidazolyl; or R b and R3, together with the atoms to which they are attached, form a pyrrolidine ring, to provide a compound of formula (I). In certain embodiments, the compound is not one of

[0052] In certain embodiments, the present invention is a compound of formula (IA)

Chemical formula

[0053] In certain embodiments, the present invention is a compound of formula (IA)

Chemical formula

[0054] In certain embodiments, R1 is hydrogen, -CH2COOH, -CH2CONH2, - CH(CH3)-CH2-CH3, -(CH2)2CONH2, -(CH2)2COOH , -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2-phenyl , -CH2-indolyl or -CH2-imidazolyl.

[0055] In certain embodiments, R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2- phenyl, or -CH2-imidazolyl.

[0056] In certain embodiments, R1 is -(CH2)2CONH2, -(CH2)2COO H, -(CH2)3NH(C=NH)NH2, or -(CH2)4NH2.

[0057] In certain embodiments, R1 is -(CH2)2CONH2, or -(CH2)2 COOH.

[0058] In certain embodiments, R2 is hydrogen, -CH2-OH, -(CH2)2CONH2 , -(CH2)3NHC(=NH)NH2, -(CH2)2COOH, or -CH2- phenyl.

[0059] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, also or -(CH2)2COOH.

[0060] In certain embodiments, R2 is hydrogen, -(CH2)2CONH2, or -(CH 2)2COOH.

[0061] In another embodiment, the present invention provides R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2-phen yl or -CH2-imidazolyl; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, or -CH2-imidazolyl, and provides a compound of formula (IA).

[0062] In certain embodiments, the present invention provides R a is hydrogen; R1 is hydrogen, -CH2-COOH, -CH2-CONH2, - CH(CH3)-CH2-CH3, -(CH2)2CONH2, -(CH2)2COOH -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2-phenyl -CH2-indolyl or -CH2-imidazolyl; said phenyl, indol yl and imidazolyl are unsubstituted; R2 is hydrogen, -CH2-OH, -(CH2)2CONH2, -(CH2)3NHC( =NH)NH2, -(CH2)2COOH, or -CH2-phenyl; said phe nyl is unsubstituted, and provides a compound of formula (IA).

[0063] In another embodiment, the present invention provides R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NH(C=NH)NH2, -CH2COOH, -CH2CONH2 , -(CH2)4NH2, -CH(CH3)-CH2-CH3, -CH2-phenyl, - CH2-indolyl or -CH2-imidazolyl; R2 is hydrogen, -CH2-OH, -(CH2)3NHC(=NH)NH2, -(CH2 )2COOH, -CH2-phenyl or -CH2-imidazolyl, to provide a compound of formula (IA).

[0064] In another embodiment, the present invention R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH(CH3 )-CH2-CH3, -CH2-phenyl, or -CH2-imidazolyl; R2 is hydrogen, -CH2-OH, -(CH2)3NHC(=NH)NH2, -(CH2 )2COOH, -CH2-phenyl or -CH2-imidazolyl, to provide a compound of formula (IA).

[0065] In another embodiment, the present invention R a is hydrogen; R1 is -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NH(C=NH)NH2, or -(CH2)4NH2; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2COOH, - CH2-phenyl or -CH2-imidazolyl, to provide a compound of formula (IA).

[0066] In certain embodiments, the compound of formula (IA) is

Chemical formula

[0067] In certain embodiments, the compound of formula (I) is

Chemical formula

[0068] In certain embodiments of the present invention, the compound of formula (IA) has the absolute stereochemistry

Chemical formula

[0069] In certain embodiments, the present invention provides a compound of formula (IB):

Chemical formula

[0070] In another embodiment, the present invention wherein R1 is hydrogen, -CH2-COOH, -CH2-CONH2, -CH(CH3)-CH 2-CH3, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NH (C=NH)NH2, -(CH2)4NH2, -CH2-indolyl, -CH2-imid azolyl or -CH2-phenyl; R b is hydrogen; R3 is hydrogen, -CH2-COOH, -CH(CH3)-CH2 -CH3, -CH2-CH(CH3)2, -(CH2)4NH2, -(CH2)2CON H2, -(CH2)2COOH, -CH2-phenyl, CH2-imidazolyl or C H2-imidazolyl; or R b is hydrogen, to provide a compound of formula (IA). In certain embodiments, in formula (IB), R b and R3, together with the atom to which they are attached form a pyrrolidine ring.

[0071] In certain embodiments, R1 is hydrogen, -CH2-COOH, -CH2-CONH2 , -CH(CH3)-CH2-CH3, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, -CH2-ind olyl, -CH2-imidazolyl or -CH2-phenyl.

[0072] In certain embodiments, R1 is hydrogen, -(CH2)2CONH2, -(CH2)2 COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, or -C H2-phenyl.

[0073] In certain embodiments, R1 is -(CH2)2CONH2 or -(CH2)2C OOH.

[0074] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)2CON represents H2 or -(CH2)2COOH.

[0075] In certain embodiments, R b is hydrogen; R3 is hydrogen, -CH2-COOH, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -(CH2)4NH 2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, CH2 -imidazolyl or CH2-imidazolyl; or R b is hydrogen. In certain embodiments, in formula (IB), R b and R3, together with the atom to which they are attached, form a pyrrolidine ring.

[0076] In certain embodiments, R3 represents hydrogen or -CH2-phenyl.

[0077] In certain embodiments, in formula (IB), R b is hydrogen. In certain embodiments in formula (IB), R b and R3, together with the atom to which they are attached, form a pyrro lidine ring.

[0078] In certain embodiments, the present invention provides a compound of formula (IB) wherein R1 represents -(CH2)2CONH2 or -(CH2)2COOH; R b is hydrogen; and R3 represents hydrogen or -CH2-phenyl; or R b and R3, together with the atom to which they are attached, form a pyrrolidine ring.

[0079] In certain embodiments, the compound of formula (I)

Chemical formula

[0080] In certain embodiments, the present invention provides a compound of formula (IC): [Chemical formula] (wherein R1, R a , R3 and R b are as defined for the compounds of formula (I)), or a pharmaceutically acceptable salt or amide or ester or stereoisomer thereof.

[0081] In certain embodiments, R1 represents -(CH2)2COOH, -(CH2)2CONH 2, -(CH2)3NH(C=NH)NH2, or -(CH2)4NH2.

[0082] In certain embodiments, R1 represents -(CH2)2CONH2, -(CH2)3NH( C=NH)NH2, or -(CH2)4NH2.

[0083] In certain embodiments, R1 represents -(CH2)2CONH2, or -(CH2)3 NH(C=NH)NH2.

[0084] In certain embodiments, in formula (IC), R a is hydrogen. In certain embodiments in formula (IC), R a and R1 together with the atom to which they are attached form a pyrro lysine ring.

[0085] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC ​​(=NH)NH2, -CH2-imidazolyl; or R b and R3 are the results Together with the atoms to which it is attached it forms a pyrrolidine ring.

[0086] In certain embodiments, R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC It represents (=NH)NH2 or -CH2-imidazolyl.

[0087] In certain embodiments, in formula (IC), R b is hydrogen. In formula (IC), R b and R3, together with the atom to which they are attached, are pyrrolo It forms a lysine ring.

[0088] In another embodiment, the present invention provides R1 is -(CH2)2COOH, -(CH2)2CONH2, -(CH2)3NH( C=NH)NH2, or -(CH2)4NH2; R3 is hydrogen, -CH2-phenyl, -(CH2)2CONH2, or -(CH2) Represents 2COOH, A compound of formula (IC) is provided.

[0089] In another embodiment, the present invention provides R a is hydrogen; and R1 is -(CH2)2CONH2, -(CH2)3NH( C=NH)NH2, or -(CH2)4NH2; or R a and R1, together with the atoms to which they are attached form a pyrrolidine ring; R b is hydrogen; and R3 is -CH2-phenyl, -(CH2)3NHC(=N H) NH2 or -CH2-imidazolyl; or R b and R3, which, together with the atoms to which it is attached, forms a pyrrolidine ring, provides a compound of formula (IC).

[0090] In another embodiment, the present invention is R a is hydrogen; and R1 is -(CH2)2CONH2, or -(CH2) 3NH(C=NH)NH2; or R a and R1, together with the atoms to which they are attached, form a pyrrolidine ring; R b is hydrogen; and R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, or -CH2-imidazolyl; or R b and R3, together with the atoms to which they are attached, form a pyrrolidine ring, provides a compound of formula (IC).

[0091] In certain embodiments, the compound of formula (I) is

Chemical formula

[0092] In certain embodiments, the present invention is a compound of formula (ID):

Chemical formula

[0093] In certain embodiments, R1 is -(CH2)3NH(C=NH)NH2, -(CH 2)4NH2, or -CH2CONH2.

[0094] In certain embodiments, R3 is hydrogen, -(CH2)3NH(C=NH)NH2, or -(CH2)4NH2.

[0095] In certain embodiments, in formula (ID), R b is hydrogen. In certain embodiments in formula (ID), R b and R3, together with the atom to which they are attached, form a pyrro lysine ring.

[0096] In certain embodiments, R b is hydrogen; and R3 is hydrogen, -(CH2)3N HC(=NH)NH2, or -(CH2)4NH2; or R b and R3 together with the atom to which they are attached, form a pyrrolidine ring.

[0097] In another embodiment, the present invention wherein R1 is -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, or -C H2CONH2; R b is hydrogen; and R3 is hydrogen, -(CH2)3NHC(=NH)NH2, or -(CH2)4NH2; or R b and R3 together with the atom to which they are attached form a pyrrolidine ring, provides a compound of formula (ID).

[0098] In another embodiment, the present invention wherein R1 is -(CH2)3NH(C=NH)NH2, -(CH2)4NH2, or -C represents H2CONH2; R b is hydrogen; and R3 is hydrogen, -(CH2)3NHC(=NH)NH2, or also represents -(CH2)4NH2; or R b and R3, together with the atom to which they are attached form a pyrrolidine ring, to provide a compound of formula (ID).

[0099] In certain embodiments, the compound of formula (I) is

Chemical formula

[0100] In certain embodiments, the present invention provides a compound of formula (IE):

Chemical formula

[0101] In certain embodiments, R2 is hydrogen, -CH2-OH, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -CH2-phenyl or -CH2-indole represents.

[0102] In certain embodiments, R2 is hydrogen or -(CH2)3NHC(=NH)NH 2 represents.

[0103] In another embodiment, the present invention wherein R2 is hydrogen, -CH2-OH, -(CH2)2COOH, -(CH2)3NHC(= represents NH)NH2, -CH2-phenyl or -CH2-indolyl; R3 is hydrogen, -(CH2)2COOH, -(CH2)2COOH, -CH2-CH( CH3)2, -CH(CH3)-CH2-CH3, -(CH2)4NH2, -CH2-f enyl, -CH2-indolyl or -CH2-imidazolyl; or R b and R3, together with the atoms to which they are attached, forms a pyrrolidine ring, to provide a compound of formula (ID).

[0104] In certain embodiments, in formula (IE), R b and R3, together with the atoms to which they are attached, form a pyrrolidine ring.

[0105] In certain embodiments, R2 is hydrogen, -(CH2)3NHC(=NH)NH2, - CH2-OH, -(CH2)2COOH, -CH2-phenyl or -CH2-indol yl.

[0106] In another embodiment, the present invention wherein R2 represents hydrogen or -(CH2)3NHC(=NH)NH2; R b and R3 together with the atoms to which they are attached, form a pyrrolidine ring, to provide a compound of formula (IE).

[0107] In certain embodiments, R3 is hydrogen, -CH2-COOH, -(CH2)2-CO OH, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -(CH2) 4NH2, -CH2-phenyl, -CH2-indolyl or -CH2-imidazolyl ; or R b and R3, together with the atoms to which they are attached, form a pyrrolidine ring​ is doing.

[0108] In certain embodiments, the present invention provides a compound of formula (IF):

Chemical formula

[0109] In certain embodiments, R2 represents hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, or -(CH2)2COOH.

[0110] In certain embodiments, R3 represents -CH2-phenyl, -(CH2)2CONH2, -(CH2)2COOH, or -(CH2)4NH2.

[0111] In certain embodiments, R3 represents -CH2-phenyl, -(CH2)2CONH2, or -(CH2)2COOH.

[0112] In certain embodiments, in formula (IF), R b is hydrogen. In certain embodiments in formula (IF), R b and R3 together with the atom to which they are attached form a pyrro lysine ring.

[0113] In certain embodiments, the present invention provides wherein R2 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, or -(CH2)2COOH; wherein R3 represents -CH2-phenyl, -(CH2)2CONH2, -(CH2)2COOH, or represents -(CH2)4NH2, to provide a compound of formula (IF).

[0114] In certain embodiments, the present invention wherein R2 is hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, or represents -(CH2)2COOH; R b is hydrogen and R3 is -CH2-phenyl, -(CH2)2CONH2, or represents -(CH2)2COOH; or R b and R3 together with the atom to which they are attached form a pyrrolidine ring, to provide a compound of formula (IF).

[0115] In certain embodiments, the compound of formula (I) is

Chemical formula

[0116] In certain embodiments, R a is hydrogen; and R1 is hydrogen, -(CH2)2C ONH2, -(CH2)2COOH, -(CH2)3NH(C=NH)NH2, -(CH 2)4NH2, -CH2CONH2, -CH2-aryl, or -CH2-heteroaryl or; or R a and R1 together with the atom to which they are attached form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-heteroaryl ; R b is hydrogen; and R3 is hydrogen, -CH2-aryl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -CH2COOH, -(CH2)4NH 2 or -CH2-heteroaryl; or R b and R3 together with the atom to which they are attached form a pyrrolidine ring.

[0117] In certain embodiments, R a is hydrogen; and R1 is hydrogen, -(CH2)2C ONH2, -(CH2)2COOH, -(CH2)3NH(C=NH)NH2, -(CH 2)4NH2, -CH2CONH2, -CH2-phenyl, or -CH2-imidazo ryl; or R a and R1 together with the atom to which they are attached form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, or -CH2-imidazolyl; R b is hydrogen; and R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC (=NH)NH2, -(CH2)2CONH2, -CH2COOH, -(CH2)4NH 2 or -CH2-imidazolyl; or R b and R3 together with the atom to which they are attached form a pyrrolidine ring.

[0118] In certain embodiments, the present invention

Table 1

[0119] In certain embodiments, the present invention [Table 2] TIFF0007698699000031.tif241162TIFF0007698699000032.tif158162or a pharmaceutically acceptable salt or amide or ester or stereoisomer thereof to provide a compound selected therefrom.

[0120] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or diluent and used for treating an individual in need thereof.

[0121] The present invention also provides a method for formulating a compound disclosed for pharmaceutical administration.

[0122] The compositions and methods of the present invention may be used to treat an individual in need thereof In certain embodiments, the individual is a mammal such as a human or non-human mammal . When administered to an animal such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising a compound of the present invention and a pharmaceutically acceptable carrier. Preferred embodiments In an embodiment, such pharmaceutical compositions are for administration to humans, particularly for invasive administration routes (i.e., , routes such as injection or implantation that avoid transport or diffusion through the epithelial barrier) if so, the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to effect delayed release of the drug or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in unit dosage forms such as tablets, capsules (such as sprinkle capsules and gelatin capsules), granules, reconstituted freeze dried products, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, such as in a skin patch. The composition can also be present in a solution suitable for topical administration, such as eye drops. can be present.

[0123] Pharmaceutically acceptable carriers can contain physiologically acceptable agents that act, for example, to stabilize the compounds of the present invention, to increase the solubility of the compounds of the present invention, or to increase absorption. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation of the pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be, for example, a liposome or other polymeric matrix that can incorporate the compounds of the present invention within it. ​​​​​​​ It is possible. For example, liposomes, which contain phospholipids or other lipids, are non-toxic, physiologically acceptable and metabolizable carriers that are relatively easy to prepare and administer.

[0124] The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without producing excessive toxicity, allergy, allergic reaction or other problems or complications and commensurate with a reasonable benefit / risk ratio. compositions and / or dosage forms and is used herein for that purpose.

[0125] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) ethyl oleate and lauryl alcohol; esters such as ethyl acetate; (13) agar; (14) magnesium hydroxide and aluminum hydroxide and other buffering agents; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical formulations, may be mentioned.

[0126] The pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration, for example, orally (e.g., as an aqueous or non-aqueous solution or suspension, drink, tablet, capsule (including sprinkle capsules and gelatin capsules), bolus, powder, granule, paste applied to the tongue); absorption through the oral mucosa (e.g., sublingually) ; transanal, rectal or vaginal (e.g., as a pessary, cream or foam); parenterally (e.g., as a sterile solution or suspension, including intramuscular, intravenous, subcutaneous or intrathecal); intranasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment or spray applied to the skin, or as an eye drop ). The compound may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. ) The formulation may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect

[0127] The formulation may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be admixed with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be admixed with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect by any method well known in the art of pharmacy. The amount of active ingredient that may be admixed with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be admixed with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect which will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be admixed with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect which will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be admixed with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect ​​will be the amount. Generally, out of 100%, this amount will be in the range of about 1% to about 99% of the active ingredient, preferably or about 5% to about 70%, most preferably about 10% to about 30%.

[0128] The method for preparing these formulations or compositions involves the step of associating an active compound such as a compound of the present invention with a carrier, and optionally one or more auxiliary components. Generally, the formulation is prepared by uniformly and closely associating the compound of the present invention with a liquid carrier or a fine solid carrier or both, and then, if necessary, shaping the product. The formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, troches (based on flavor, usually using sucrose and acacia or tragacanth), lyophilized products, powders, granules, each containing a predetermined amount of the compound of the present invention as an active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a perfume (using an inert base such as gelatin and glycerin or sucrose and acacia) and / or a mouthwash, etc. The composition or compound may also be in the form of a bolus, a lozenge or a paste. To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is, for example, sodium carboxymethylcellulose or dicalcium phosphate and / or any of the following

[0129]

[0130] ​ 、 admixed with one or more pharmaceutically acceptable carriers: (1) fillers or extenders such as starch, lactose , sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Tablets may be made, optionally with one or more accessory ingredients, by

[0131] compression or molding. Compressed tablets may contain binders (such as, for example, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as, for example, starch glycolate Sodium acid, or cross-linked sodium carboxymethyl cellulose), a surfactant or It may be prepared using a dispersant. The molded tablets are of a powdered compound moistened with an inert liquid diluent It may also be produced by molding a mixture with a suitable machine.

[0132] Tablets and other solid dosage forms of pharmaceutical compositions such as syrups, capsules (including sprinkle capsules and gelatin capsules), pills and granules may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well-known in the art of pharmaceutical formulation They may also be formulated to provide a desired release profile for example, by using hydroxypropylmethylcellulose in various proportions to provide sustained or controlled release of the active ingredient, other polymer matrices, liposomes and / or microspheres They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and, optionally, in a delayed manner, release the active ingredient(s) only at or preferentially at a specific site in the gastrointestinal tract Compositions may be. Examples of implantable compositions that may be used include polymeric substances and waxes. The active ingredient may also, as appropriate, be in microencapsulated form with one or more of the above excipients.

[0133] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, reconstructions ​​​​Examples include freeze-dried products, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may, in addition to the active ingredient, contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also contain, in addition to the inert diluent, adjuvants such as wetting agents, emulsifying and

[0134] suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents and preservatives.

[0135] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, tragacanth, and mixtures thereof. Compositions for rectal, vaginal or urethral administration may be presented as suppositories,

[0136] which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature. It is a liquid and will thus melt in the rectal or vaginal cavity and release the active compound.

[0137] The formulation of the pharmaceutical composition for oral administration may be provided as a mouthwash or an oral spray or an oral ointment and may be provided as such.

[0138] Alternatively or additionally, the composition may be formulated for delivery via a catheter, stent, wire or other tube intracavitary device. Delivery via such a device may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine. Delivery via such a device may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0139] Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing carriers known to be appropriate in the art. formulations containing carriers known to be appropriate in the art.

[0140] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams lotions, gels, solutions, patches and inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier under sterile conditions and any preservatives, buffers or propellants that may be required. and any preservatives, buffers or propellants that may be required.

[0141] Ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof, in addition to the active compound. Ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof, in addition to the active compound. Ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof, in addition to the active compound. Ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof, in addition to the active compound.

[0142] Powders and sprays may contain lactose, talc, silicic acid, aluminum hydroxide, in addition to the active compound. It may contain excipients such as aluminum, calcium silicate, and polyamide powder, or a mixture of these substances. In addition, the spray may contain conventional propellants such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

[0143] The transdermal patch has the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms are prepared by dissolving or dispersing the active compound in a suitable medium. The absorption enhancer can also be used to increase the permeation of the compound through the skin. The rate of such permeation can be controlled either by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0144] As used herein, the terms "parenteral administration" and "administered parenterally" usually mean a mode of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intracranial, intrasynovial, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, trans-tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0145] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted immediately prior to use into sterile injectable solutions or dispersions, and may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0146] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, to maintain the particle size required in the case of dispersions, and by the use of surfactants.

[0147] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. In addition, prolonged absorption of injectable pharmaceutical forms may be

[0148] brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. In some instances, it is desirable to slow the absorption of a drug from subcutaneous or intramuscular injection in order to extend the effect of the drug. This may be accomplished by the use of a liquid suspension of a crystalline or amorphous material having poor water solubility. In that case, the rate of

[0149] Injectable depot forms are prepared by forming a microencapsulation matrix of the title compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer and the nature of the individual polymers used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by encapsulating the drug in a liposome or microemulsion that is compatible with body tissues. For use in the method of the present invention, the active compound can be administered as such or in combination with a pharmaceutically acceptable carrier, for example, as a pharmaceutical composition containing 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient. The method of introduction may also be provided by a refillable or biodegradable device. Various sustained-release polymer devices, including proteinaceous biopharmaceuticals, have been developed and tested in vivo for controlled drug delivery in recent years. Implants for the sustained release of compounds at individual target sites can be formed using various biocompatible polymers (such as hydrogels), including both biodegradable and non-degradable polymers. The actual dosage level of the active ingredient in the pharmaceutical composition may vary to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response without being toxic to the patient, and is effective in relation to the individual patient, composition, and mode of administration. The dosage level selected will depend on the particular compound or combination of compounds used, or

[0150]

[0151]

[0152]

[0153] ​ The activity of the ester, salt or amide, the route of administration, the time of administration, the individual compounds used (s), the rate of excretion, the treatment period, other drugs, compounds and / or materials used in combination with the specific compound(s) used The age, sex, weight, disease, general health status and past medical history of the patient being treated, as well as various factors including similar factors well known in the medical art will depend on factors such as will depend on various factors including the activity of the ester, salt or amide, the route of administration, the time of administration, the individual compounds used (s), the rate of excretion, the treatment period, other drugs, compounds and / or materials used in combination with the specific compound(s) used, the age, sex, weight, disease, general health status and past medical history of the patient being treated, as well as similar factors well known in the medical art.

[0154] Generally, the appropriate daily dosage of the active compounds used in the compositions and methods of the present invention will be the amount of the compound that is the minimum dosage effective to produce a therapeutic effect. Such effective dosages generally depend on the factors described above. If desired, the effective daily dosage of the active compound may be administered separately, in one, two, three, four, five, six, or more divided doses, at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day. will generally depend on the factors described above.

[0155] If desired, the effective daily dosage of the active compound may be administered separately, in one, two, three, four, five, six, or more divided doses, at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day. will generally depend on the factors described above. The patient to be treated may be any animal in need thereof, including primates, particularly humans, and other mammals such as cows, pigs, sheep, and horses, and generally includes poultry and pets. will generally depend on the factors described above. will generally depend on the factors described above.

[0156] The patient to be treated may be any animal in need thereof, including primates, particularly humans, and other mammals such as cows, pigs, sheep, and horses, and generally includes poultry and pets. will generally depend on the factors described above. will generally depend on the factors described above.

[0157] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition. will generally depend on the factors described above. will generally depend on the factors described above.

[0158] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; ( 2) fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hy droxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0159] In certain embodiments, the compounds described herein increase the phagocytic activity of macrophages directed against cancer cells, such as AML cells. In other embodiments, the phagocytic activity is increased, for example, by 1 %, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to macrophages in the absence of the compounds described herein.

[0160] In certain embodiments, the present invention provides for the use of the compounds of the present invention for the preparation of a medicament.

[0161] In certain embodiments, the present invention provides for the use of the compounds of the present invention for the preparation of a medicament, for example, for the treatment of cancer.

[0162] In certain embodiments, the present invention provides a method for treating cancer, the method comprising administering to a subject in need thereof a compound of the present invention, for example, in a therapeutically effective amount.

[0163] In certain embodiments, the present invention administers to a subject in need thereof, for example, in a therapeutically effective amount, the present invention A method for inhibiting the growth and / or metastasis of tumor cells by administering a compound of is provided.

[0164] In certain embodiments, the invention relates to a method for treating cancer, R a is hydrogen; and R1 is hydrogen, -(CH2)2CONH2, -(CH2)2C OOH, -CH2COOH, -(CH2)3NH(C=NH)NH2, -(CH2)4N H2, -CH2CONH2, -CH(CH3)-CH2-CH3, -CH2-aryl, or -CH2-heteroaryl; said aryl and heteroaryl are unsubstituted; or R and R1 together with the atom to which they are attached form a pyrrolidine ring optionally substituted with an oxo group; a R2 is hydrogen, -CH2-OH, -(CH2)3NHC(=NH)NH2, -(CH2 )2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-hetero aryl; said aryl and heteroaryl are unsubstituted; R is hydrogen; and R3 is hydrogen, -CH2-aryl, -(CH2)3NHC (=NH)NH2, -CH2COOH, -CH(CH3)-CH2-CH3, -CH2- b CH(CH3)2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2) (=NH)NH2 or -CH2-heteroaryl; said aryl and heteroaryl are unsubstituted; or R and R3 together with the atom to which they are attached form a pyrrolidine ring, b is provided, a compound of formula (I), or a pharmaceutically acceptable salt or amide or ester or stereoisomer thereof. ​​

[0165] Representative tumor cells include, without limitation, melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia chronic or acute leukemia such as chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer renal pelvis cancer, central nervous system (CNS) neoplasms, non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, B cell lymphoma, environmentally induced cancers (e.g., mesothelioma) induced by asbestos, and combinations of the above cancers including cancer cells. In certain embodiments, the present invention provides the use of the compounds of the present invention for preparing agents for the treatment of bacterial, viral and fungal infections, as well as methods of administering the compounds of the present invention, for example, in a therapeutically effective amount, for the treatment of bacterial, viral or fungal infections.

[0166] In yet another embodiment of the present invention, there is provided a method of treating an infection by blocking the CD-47 pathway, which comprises administering to a subject in need thereof, for example, in a therapeutically effective amount, a compound of the present invention.

[0167]

[0168] In certain embodiments, the invention provides for the use of the compounds of the invention in inhibiting the CD-47 pathway.

[0169] In certain embodiments, the invention provides a method for treating an infectious disease in a subject, comprising administering a compound of the invention, e.g., in a therapeutically effective amount.

[0170] Representative infectious diseases include HIV, influenza, herpes, giardia, malaria, leishmania, hepatitis viruses (A, B, & C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and pathogenic infections by arbovirus encephalitis virus, cryptococcus, rickettsia, mycobacterium, staphylococcus, streptococcus, pneumococcus, meningococcus, and gonococcus, klebsiella, proteus, serratia, pseudomonas, escherichia coli, legionella, diphtheria, salmonella, bacillus, cholera, clostridium tetani, clostridium botulinum, bacillus anthracis, yersinia pestis, leptospira, and listeria pathogenic infections by candida fungi (albicans, krusei, glabrata, tropicalis, etc.), cryptococcus neoformans, aspergillus (fumigatus, , such as Nigel), Mucorales (Mucor, Absidia, Rhizopus), Sporothrix S. shenkii, Blastomyces dermatitidis, Paracoccidioides brasili ensis, Coccidioides immitis and pathogenic infections caused by Histoplasma capsulatum , as well as pathogenic infections caused by Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba species, Giardia lamblia, Cryptosporidium species, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma go ndii, pathogenic infections caused by Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Schistosoma mansoni, Schistosoma japonicum, Schistosoma haematobium, Clonorchis sinensis, Fasciola hepatica, Taenia solium, Taenia saginata, Echinococcus granulosus, Echinococcus multilocularis, Hymenolepis nana, Diphyllobothrium latum, Paragonimus westermani, and other parasites are included, but not limited to these.

[0171] In certain embodiments, the present invention provides a method for treating or delaying the progression of atherosclerosis and multiple sclerosis mediated by CD47 in an individual, comprising administering to the individual an effective amount of a compound of formula (I). In certain embodiments, the present invention provides a method for treating atherosclerosis and multiple sclerosis in a subject, comprising administering a therapeutically effective amount of a compound of formula (I). The compound may be used alone or, preferably, in a pharmaceutical composition in which the compound is mixed with one or more pharmaceutically acceptable materials.

[0172] The term "treating" encompasses prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is recognized in the art and refers to the administration of one or more of the subject compositions to a host for the purpose of preventing and / or treating a disease or condition.

[0173] The compound may be used alone or, preferably, in a pharmaceutical composition in which the compound is mixed with one or more pharmaceutically acceptable materials.

[0174] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is recognized in the art and refers to the administration of one or more of the subject compositions to a host comprises a plurality of administrations. When it is administered prior to the clinical manifestation of an undesirable condition (e.g., a disease of the host animal or other undesirable situation), the treatment is prophylactic (i.e., it protects the host from developing an undesirable disease), while when it is administered after the manifestation of an undesirable disease, the treatment is therapeutic (i.e., it is intended to eliminate, ameliorate or stabilize an existing undesirable disease or its side effects).

[0175] As used herein, the term "compound(s)" includes compounds of formula (I), (IA), (IB), ( IC), (ID), (IE), (IF), and pharmaceutically acceptable salts or stereoisomers thereof.

[0176] As used herein, the term "aryl", unless otherwise specified, includes substituted or unsubstituted monocyclic aromatic groups wherein each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more cyclic compounds wherein two or more carbons are common to two adjacent rings and at least one of the rings is aromatic, e.g., other cyclic compounds can be cyclo alkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, etc. Preferably the term " aryl" includes phenyl.

[0177] The term "heteroaryl", unless otherwise specified, includes substituted or unsubstituted aromatic monocyclic structures preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, and the ring structure contains at least also contains one heteroatom, preferably from 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "heteroaryl" also refer to two or more carbons are common to two adjacent rings, and at least one of the rings is heteroaromatic, for example, other cyclic compounds can be cycloalkyl, cycloalkenyl, cycloalkynyl, alyl -yl, heteroaryl and / or heterocyclyl, and include polycyclic systems having two or more cyclic compounds. Examples of heteroaryl groups include, for example, pyrrole, furan, thio phen, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, indole, 1,2,4-oxadiazole, 1,3,4-oxadiazole l, 1,3,4-thiadiazole, benzimidazole, pyrimidine and the like. The heteroaryl group may be substituted at one or more positions with any optional substituents described herein as permitted by valence.

[0178] The term "acyl" is recognized in the art and refers to a group represented by the general formula alkyl-C(O)-. Examples of "acyl" groups are acetyl, propionyl and butyryl but are not limited thereto.

[0179] A therapeutic agent that "prevents" a disorder or disease as used herein is a compound that reduces the incidence of a disorder or disease in a treated sample compared to an untreated control sample in a statistical sample or delays the onset or reduces the severity of one or more symptoms of a disorder or disease compared to an untreated control sample.

[0180] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic" or therapeutic" treatment is recognized in the art and includes one or more administrations of the subject compositions to a host. If it is administered prior to the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable situation in a host animal), the treatment is prophylactic (i.e., it protects the host from developing the undesirable condition), while if it is administered after the manifestation of an undesirable condition, the treatment is therapeutic (i.e., it

[0181] is intended to eliminate, ameliorate or stabilize the existing undesirable condition or its side effects). As used herein, the phrase "delaying progression" refers to a procedure or application

[0182] intended to delay the onset time of a disease or symptoms of a disease (including delaying the appearance or occurrence time of at least one symptom of an individual disease). The term "prodrug" shall include compounds which are converted into the therapeutically active agents of the present invention under physiological conditions (e.g., compounds of formula (I)). General methods for making prodrugs are to include one or more selected moieties which are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is Roxyl is shown as an ester, or a carboxylate or carboxylic acid present in the parent compound is shown as an ester. is shown as an ester.

[0183] As used herein, the term "comprising" or "comprises" generally means including one or more additional (unspecified) features or components, in other words, allowing the presence of the features or components, and is used in that sense.

[0184] As used herein, the term "comprising" and other forms, such as "include", "includes", and "included", are not limiting.

[0185] As used herein, the term "disease" or "disorder" refers to a pathological condition in an organism resulting from or caused by a disease, including but not limited to infections, acquired diseases, genetic diseases, and characterized by identifiable symptoms. Diseases and disorders also include those induced by the absence of a compound such as a TIGIT modulator.

[0186] As used herein, a "patient" or "subject" or "individual" to be treated includes humans and non-human animals including mammals. Mammals include primates such as humans, chimpanzees, gorillas and monkeys; domestic animals such as dogs, horses, cats, pigs, goats, cows; and rodents such as mice, rats, hamsters and guinea pigs.

[0187] The present invention includes pharmaceutically acceptable salts of the compounds of the present invention, as well as their use in the compositions and methods of the present invention. In certain embodiments, Examples include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Pharmaceutically acceptable acid addition salts may also exist as various solvates in water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of such solvates is derived from the crystallization solvent and may be inherent in or foreign to the crystallization solvent. As used herein, the term "pharmaceutically acceptable salt" is intended to include all salts known and used in the art of pharmaceuticals. Pharmaceutically acceptable salts include, but are not limited to, chloroprocaine, choline, N,N-dibenzylethylenediamine, ammonia, diethylamine, Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals.

[0188] Pharmaceutically acceptable acid addition salts may also exist as various solvates in water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of such solvates is derived from the crystallization solvent and may be inherent in or foreign to the crystallization solvent. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals.

[0189] As used herein, the term "pharmaceutically acceptable salt" is intended to include all salts known and used in the art of pharmaceuticals. Pharmaceutically acceptable salts include, but are not limited to, chloroprocaine, choline, N,N-dibenzylethylenediamine, ammonia, diethylamine, Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Examples include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and salts of aluminum. In certain embodiments, salts contemplated for use in the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Ethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl Glucamine, procaine, N-benzylphenethylamine, 1-parachlorobenzyl-2 -pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines amine salts such as diamine, piperazine and tris(hydroxymethyl)aminomethane; Alkali metal salts, including but not limited to lithium, potassium and sodium; alkaline earth metal salts such as, but not limited to, zinc, calcium and magnesium; Transition metal salts; other metals such as, but not limited to, sodium hydrogen phosphate and disodium phosphate salts; and salts of mineral acids, such as, but not limited to, hydrochlorides and sulfates; and acetates. , lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate Examples of salts of organic acids include, but are not limited to, salts of organic acids such as valerate and fumarate. Exemplary pharma- ceutically acceptable salts include those which have been modified to improve solubility or hydrolysis characteristics. It may be used as a dosage form or in sustained release or prodrug formulations. Acetate, lactobionate, benzenesulfonate, laurate, benzoate , malate, bicarbonate, maleate, hydrogen sulfate, mandelate, hydrogen tartrate, Mesylate, borate, methyl bromide, methyl nitrate, calcium edetate, methyl sulfate Acid salts, camsylates, mucates, carbonates, napsylates, bromides, chlorides, nitrates, chlorates Lavranate, N-Methylglucamine, Citrate, Ammonium Salt, Dihydrochloride, Oleate Phosphate, edetate, oxalate, edisylate, pamoate (embonate), estrus Salts, Palmitates, Esylates, Pantothenates, Fumarates, Phosphates / Diphosphates , gluceptate, polygalacturonate, gluconate, salicylate, glutamate salt, stearate, glycolylarsanilate, sulfate, hexylresorcinate, salt basic acetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate salt, hydroxynaphthoic acid, theobromine, iodide, tosylate, triethiodide, lactate salt, panoate and valerate are included. The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “P harmaceutical Salts,” J. Pharm. Sci. 66:1-19 (1977).

[0190] In certain preferred embodiments, the present invention includes pharmaceutically acceptable salts of the compounds of the present invention, as well as their use in the compositions and methods of the present invention. In certain embodiments , the salts of the present invention contemplated include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkylammonium salts. In certain embodiments , the salts of the present invention contemplated include, but are not limited to, L-arginine, benethamine, benzathine , betaine, calcium hydroxide, choline, deanol, diethanolamine, diethyla mine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magne sium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine and Examples of zinc salts include, but are not limited to, these. In certain embodiments, salts of the present invention contemplated include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals.

[0191] Pharmaceutically acceptable acid addition salts can also exist as various solvates in water, methanol, ethanol, dimethylformamide etc. Mixtures of such solvates can also be prepared. The source of such solvates is derived from the crystallization solvent and is inherent in or can be foreign to the solvent for preparation or crystallization.

[0192] The term "stereoisomer" refers to any enantiomer, diastereoisomer or geometric isomer of a compound of the present invention. When the compounds of the present invention are chiral, they can exist as racemates or optically active forms. Since the pharmaceutical activities of the racemates or stereoisomers of the compounds according to the present invention can be different, it may be desirable to use a compound enriched in one of the enantiomers. In these cases, the final product or even the intermediate can be separated into enantiomeric compounds by chemical or physical procedures known to those skilled in the art or used in synthesis etc. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoyl proline or N-benzenesulfonylproline) or optically active acids such as the R and S forms of various optically active camphorsulfonic acids. Also advantageous is the optically active resolving agent ( For example, dinitrobenzoylphenylglycine, cellulose triacetate fixed on silica gel, or other carbohydrate derivatives, or chiral derivatized methacrylate polymers) is enantiomeric resolution by chromatography with the aid of an auxiliary.

[0193] As used herein, the term "ester" refers to the group -C(O)OR 11 (wherein R 11 represents a hydrocarbyl group).

[0194] As used herein, the term "amide" refers to the group -C(O)NH2.

[0195] In certain embodiments, the compounds of the invention may be racemic. In certain embodiments the compounds of the invention may be enriched in one enantiomer. For example, the compounds of the invention may have 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80 % ee, 90% ee or even 95% ee or more. In certain embodiments the compounds of the invention may have more than one stereocenter. In certain such embodiments, the compounds of the invention may be enriched in one or more diastereomers. For example, the compounds of the invention may have 30% de, 40% de, 50% de , 60% de, 70% de, 80% de, 90% de or even 95% de or more .

[0196] The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wild animals).

[0197] The abbreviations used throughout the specification can be summarized below along with their respective meanings. °C (degrees Celsius); % (percent value); ACN (acetonitrile), brine (NaCl solution) ; CH2Cl2 / DCM (dichloromethane); BOC (tert-butyloxycarbonyl) ; DIC: N,N’-diisopropylcarbodiimide; DMF (dimethylformamide) ; EtOH (ethanol); Et2NH (diethylamine); ECF (ethyl chloroformate), Fmoc: (9-fluorenylmethyloxycarbonyl); g or gr (gram) ; h or hr (hour); HPLC (high performance liquid chromatography); K2CO 3 (potassium carbonate); LCMS (liquid chromatography - mass spectrometry); nmol (nanomole) ; M (molar); μl (microliter); mL (milliliter); mg (milligram) ; min (minute); NaHCO3 (sodium bicarbonate); NMM (N-methylmorpholine) ; Na2SO4 (sodium sulfate); NH3 (ammonia); NH2OH.H Cl (hydroxylamine hydrochloride); prep-HPLC / preparative HOBt (hydroxybenzotriazole); HPLC (preparative high performance liquid chromatography); TEA / Et3N (triethylamine); THF (tetrahydrofuran); TFA (trifluoroacetic acid); ; TFAA (trifluoroacetic anhydride), TIPS (triisopropylsilane); t (retention time). R (Retention time).

[0198] Experiment The present invention provides a method for preparing the compound of formula (I) according to the procedures of the following examples using suitable materials. Using the conditions and known variations of the following preparation procedures, this Those skilled in the art will understand that the compounds can be prepared. Moreover, by using the procedures described in detail Those skilled in the art can prepare additional compounds of the present invention.

[0199] The intermediates or starting materials required for the synthesis are either commercially available (Sigma-Aldri ch (USA or Germany); Chem-Impex (USA); G.L.Biochem( China), and commercial suppliers such as Spectrochem (India)), or these intermediates or starting materials can be prepared using the methods in known literature. The present invention will be described in more detail by specific examples.

[0200] HPLC method for analysis: Method-1: Column: ZIC-HILLIC (Sequant), C18 (4.6×250mm, 5 μm) 200A° Flow rate: 1.0 mL / min; Column temperature: 25.0 °C Mobile phase: A = 5 mM ammonium acetate PH-4.0 (acetic acid), IACN Gradient (Tim / %b): 0 / 85, 2 / 85, 20 / 40, 20.1 / 85, 30 / 85 .

[0201] Method 2: Column: Phenomenex Aeris peptide C18(2) 100A( 250×4.6mm, 3.6μ) Flow rate: 1.0 mL / min; Column temperature: 25.0 °C Mobile phase: A = 0.1% TFA (Aq), B = ACN Gradient (Time / % b): 0 / 2, 2 / 2, 15 / 70, 20 / 95, 25 / 100, 30 / 100, 32 / 2, 42 / 2

[0202] Preparative HPLC method: Fractional HPLC was performed using a Phenomenex Luna 5μ 100A° column (250 m m × 21.2 mm, 5 μm) at a flow rate of 15.0 mL / min. The elution conditions used were: buffer A: 0.1% formic acid in water, buffer B: acetonitrile, equilibration of the column with 0% buffer B, and elution with a gradient of buffer B from 0% to 10% over 30 minutes.

[0203] LCMS was performed using a Mercury MS column with an AP1 2000 LC / MS / MS triple quadrupole and an Agilent 1100 series HPLC and G1315 B DAD, or using a Mercury MS column with an Agilent LC / MSD VL single quadrupole and an Agilent 1100 series HPLC and G1315 B DAD, or using a Shimadzu LCMS 2020 single quadrupole and a Prominence UFLC system and an SPD-20 A DAD.

[0204] LCMS was performed using a Mercury MS column with an AP1 2000 LC / MS / MS triple quadrupole (Applied biosystems) and an Agilent 1100 series HPLC and G1315 B DAD, or using a Mercury MS column with an Agilent LC / MSD VL single quadrupole and an Agilent 1100 series HPLC and G1315 B DAD, or using a Shimadzu LC MS 2020 single quadrupole and a Prominence UFLC system and an SPD-2 0 A DAD.

[0205] Embodiments of the present invention are carried out according to the procedures of the following example(s) using appropriate materials in the formula ( ​​Provide the preparation of the compounds of (I). It will be understood by those skilled in the art that these compounds can be prepared using the conditions and known modifications of the following preparation procedures. Moreover, by using the procedures described in detail, those skilled in the art will be able to prepare additional compounds of the present invention. Furthermore, it will be understood by those skilled in the art that these compounds can be prepared using the conditions and known modifications of the following preparation procedures. Moreover, by using the procedures described in detail, those skilled in the art will be able to prepare additional compounds of the present invention. can.

[0206] Starting materials are generally available from commercial suppliers such as Sigma-Aldrich (India or Germany); Combi -Blocks (USA), Ark Pharm (USA), Chem-Impex (USA) ; G.L.Biochem (China), and Spectrochem (India), etc. commercial suppliers.

[0207] Example 1: (((S)-4-Amino-1-(3-((S)-1,5-diaminopentyl) -1,2,4-oxadiazol-5-yl)-4-oxobutyl)carbamoyl)-L- proline (Compound 1)

Chemical formula

[0208] Synthesis of Compound 1b

Chemical formula

[0209] Synthesis of compound 1c [Chemical formula] Trifluoroacetic anhydride (6.85 mL, 48.6 mmol) was added to a solution of compound 1b (5.6 g, 16.2 mmol), pyridine (7.84 mL, 97. 2 mmol) in DCM (60 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and CH2Cl2. The organic phase was washed with a NaHCO 3 solution, followed by a citric acid and brine solution. The separated organic layer was dehydrated with Na 2SO4, filtered, and evaporated under reduced pressure to give 5.42 g of compound 1c, which was used directly in the next step.

[0210] Synthesis of compound 1d [Chemical formula] Hydroxylamine hydrochloride (3.43 g, 49.5 mmol), water (10 mL), and K 2CO3 (4.54 g, 32.9 mmol) were added to a solution of compound 1c ( 5.4 g, 16.5 mmol) in EtOH (60 mL), and the mixture was stirred at room temperature overnight. Completion of the reaction was confirmed by TLC analysis. After completion of the reaction, the compound from water was extracted by using CH2Cl2, and then the organic layer was washed with water and brine and concentrated under reduced pressure to give 5.8 g of ​​​Compound 1d was produced. LCMS: 361.3 [M+H] + .

[0211] Synthesis of Compound 1f [Chemical Structure] HOBt (3.24 g, 24.0 mmol) and DIC (3.36 mL, 24.0 m mol) were added to a solution of Fmoc-Gln(Trt)-OH (Compound 1e) (9.83 g, 16.1 mmol) in DMF (100 mL) at 0 °C and stirred for 15 minutes. Compound 1d (5.8 g, 16.1 mmol) was added to the reaction product at the same temperature, and the resulting mixture was stirred at the same temperature for 1 hour and then further stirred at room temperature for 2 hours. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice water, and the precipitated white solid was filtered, washed with water( 150 mL), and dried under high vacuum to yield 8.62 g of Compound 1f. LCMS : 953.7 [M+H] + .

[0212] Synthesis of Compound 1g [Chemical Structure] Acetic acid (5 mL) was added to a solution of Compound 1f (5.0 g, 5.0 mmol) in acetonitrile (50 ml) at room temperature, and the reaction product was refluxed at 85 °C for 12 hours. Completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain a crude semi-solid, which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO3 solution and then with citric acid and brine solutions. The organic layer was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude solid. The compound was purified using column chromatography to give 4.3 g The title compound was obtained. LCMS: 935.6 [M+H] + 。

[0213] Synthesis of Compound 1h

Chem.

[0214] Synthesis of Compound 1i

Chem.

[0215] Synthesis of Compound 1j [Chem.] TEA (0.34 mL, 2.46 mmol) was added to a solution of H-Pr in THF (10 mL) at room temperature o-O t Bu.HCl (0.21 g, 1.23 mmol) and Compound 1i (0.72 g , 0.82 mmol), and the mixture was stirred for 12 hours. The volatiles were evaporated, and the residue was partitioned between ethyl acetate and water. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude compound was purified by column chromatography and eluted with 50% ethyl acetate in hexane to give 0.5 g of Compound 1j. LCMS: 910.6 [M+H] + .

[0216] Synthesis of Compound 1 [Chem.] Compound 1j (0.5 g, 0.55 mmol) was added to a cocktail mixture of TFA:TIPS:H2O (95:2 .5:2.5) (10 mL), and the mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether, and filtered to give 0.2 g of crude Compound 1. The crude material was purified by preparative HPLC as described under the experimental conditions . LCMS: 412.2 [M+H] + . HPLC t R (min): 9.6

[0217] The following compounds were prepared by a procedure similar to that described in Example 1 (Compound 1) by appropriately changing the reactants, reagent amounts, solvents, and reaction conditions . The characterization data of the compounds are ​​​​Summarized in the following table of this specification.

Table 3

[0218] Example 2: (S)-4-(3-((S)-1-Amino-4-guanidinobutyl)-1,2, 4-oxadiazol-5-yl)-4-(3-((S)-1-carboxy-2-phenyl ethyl)ureido)butanoic acid (Compound 7)

Chemical formula

[0219] Synthesis of Compound 2b

Chemical formula

[0220] Synthesis of Compound 2c

Chemical formula

[0221] Synthesis of compound 2d

Chemical formula

[0222] Synthesis of compound 1e

Chemical formula

[0223] Synthesis of Compound 2g

Chemical Structure

[0224] Synthesis of Compound 2h [Chemical formula] Compound 2g (5.4 g, 5.80 mmol) was added to a solution of 50% piperidine in DMF (20 mL) at 0 °C and stirred at the same temperature for 2 hours. Completion of the reaction was confirmed by TLC analysis. The reaction product was quenched with water (100 mL), and the resulting precipitate was filtered. The obtained solid was dissolved in ethyl acetate, and the organic layer was washed with 10% NaHCO3, water, and brine. The organic layer was dehydrated over Na2SO4 and concentrated under reduced pressure. The resulting crude product was diluted with hexane, and the resulting precipitate was filtered and washed with hexane to obtain 3.0 g of compound 2h. LCMS 708.6 [M+H] + .

[0225] Synthesis of Compound 2i [Chemical formula] Pyridine (0.75 mL, 9.3 mmol) was added to a solution of H-Phe-OtBu.HCl (2.0 g, 7.75 mmol) in CH2Cl2 (20 mL), and pyridine was added. The resulting solution was stirred at room temperature for 10 minutes. To this reaction mixture, a solution of 4-nitrophenyl chloroformate (1.87 g, 9.30 mmol) in CH2Cl2 (20 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction (confirmed by TLC), it was diluted with CH2Cl2 (50 mL) and washed with water (100 mL × 2), 10% citric acid (100 mL × 2), water (100 mL), and then brine solution (100 mL). he-O t Bu.HCl The organic layer was dehydrated over Na2SO4, filtered, and evaporated under reduced pressure to yield 1.7 g of compound 2i, which was taken on to the next step without further purification. ​

[0226] Synthesis of Compound 2j [Chemical formula] TEA (0.29 mL, 2.1 mmol) was added to a solution of Compound 2 h (1.0 g, 1.41 mmol) and Compound 2i (0.54 g, 1.41 mmol) in THF (10 mL) at room temperature, and the mixture was stirred for 3 hours. The volatiles were evaporated and the residue was partitioned between EtOAc and water. The reaction mixture was diluted with ice-cold water and extracted with EtOAc, then washed with 10% K2CO3 (100 mL × 4), water, and brine solution. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was diluted with hexane, and the precipitate obtained was filtered and washed with hexane to yield 0.98 g of Compound 2j. LCMS: 955.6 [M+H] + .

[0227] Synthesis of Compound 7 [Chemical formula] Compound 2j (0.5 g, 5.2 mmol) was added to a cocktail mixture of trifluoroacetic acid: TIPS: water (95 : 2.5: 2.5) (5 mL). The cleavage solution was stirred at room temperature for 3 hours. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether, and filtered to yield 0.34 g of crude Compound 2. The crude solid material was purified by preparative HPLC method described under the experimental conditions. LCMS: 491.1 [M+H] + . HPLC t R : (min): 11.1

[0228] The following compounds were prepared by appropriately modifying the reactants, reagent amounts, solvents, and reaction conditions as in Example 2 It was prepared by a procedure similar to that described for Compound 7). The characterization data of the compound is summarized in the following table of this specification. [Table 4] TIFF0007698699000056.tif83162

[0229] The following compounds were also prepared by a procedure similar to that described for Example 1 (Compound 1), with appropriate modifications to the reactants, reagent amounts, solvents, and reaction conditions. The characterization data of the compound is summarized in the following table of this specification. [Table 5] TIFF0007698699000058.tif247162TIFF0007698699000059.tif221162TIFF0007698699000060.tif189162

[0230] The following compounds were also prepared by a procedure similar to that described for Example 2 (Compound 7), with appropriate modifications to the reactants, reagent amounts, solvents, and reaction conditions. The characterization data of the compound is summarized in the following table of this specification. [Table 6] TIFF0007698699000062.tif159162

[0231] Example - 3: Rescue rate of phagocytosis (%) Reagents DPBS (Gibco), RPMI 1640 containing HEPES and L - GLN (50 0 mL) (Lonza), recombinant human M - CSF (R & D systems), CD4 7 monoclonal antibody (B6H12), functional grade antibody (Ebioscience), Mouse IgG1 kappa isotype control, functional grade (Ebioscience), Vacutainer (multi-sample luer adapter) (BD), Vacutain er (heparin sodium (NH) 158 USP units, blood collection tube (BD), Histopa que (specific gravity -1.077 gm / ml) (SIGMA 1077), trypan blue solution (SIGMA-T8154), hemacytometer (Bright line-SIGMA Z359629), scalp vein infusion set (JMS), cell dissociation buffer (Gibco), 4 8-well sterile flat-bottom plate (Corning), luciferase-expressing Raji cells (Ra ji cells prepared in-house by transfection of the luciferase gene in Raji cells) luminol meter, hygromycin B (Invitrogen), Bright Glo luciferase assay system (Promega), 96-well plate, polystyrene, high band, white flat-bottom well (Sigma CLS3912), APC anti-mouse / human CD1 1b antibody (Biolegend), H929 cells, CFSE (Ebioscience) , fetal bovine serum (Gibco Cat#:10437028), round-bottom FACS tube ( BD), flow cytometer BD FACS Verse, 96-well plate, ultra-low attachment (Corning).

[0232] Protocol - 1: Luciferase-based phagocytosis assay An in vitro phagocytosis assay was performed to evaluate the ability of test items to enhance the phagocytic activity of macrophages. Monocytes were isolated from the blood of healthy donors and cultured in 10% RPMI (Ros well Park Memorial Institute) medium and recombinant human M- Cultured for 6 - 8 days using CSF and differentiated into macrophages. The medium was changed every other day. After differentiation, the adherent macrophages were collected by gentle scraping and cultured overnight at a density of 100,000 cells per well in a 48 - well tissue culture plate in 10% RPMI. Meanwhile, luciferase - expressing Raji cells were cultured in a tissue culture flask in 10% RPMI medium containing 1 00 μg / mL hygromycin B. On the day of phagocytosis, the macrophages were serum - free for 2 hours. 400,000 luciferase - expressing Raji cells per well were incubated at 37 °C for 30 minutes in serum - free medium with anti - human CD47 purified B6H12 or mouse Ig G1 K isotype control antibody or various concentrations of test items and then added to each well of the 48 - well plate seeded with macrophages. After 2 hours, the cells were washed twice with PBS and 100 μL of serum - free RPMI was added to each well. In addition, after adding 50 μL of Bright Glow reagent to each well, the cells were mixed and incubated in the dark for 5 minutes. After transferring the contents of each well to a white plate, luciferase reading was performed using a plate reader. The luminescence intensity indicated the degree of phagocytosis. Each experimental condition was performed in duplicate. The results of the selected compounds of the present invention are given in the following table.

Table 7

[0233] Protocol - 2: FACS - based phagocytosis assay Monocytes were isolated from the blood of healthy donors and cultured for 6 - 8 days using 10% RPMI (Roswell Park M emorial Institute) medium and recombinant human M - CSF. Cultured during the day and differentiated into macrophages. The medium was changed every other day. At the same time, H9 29 cells were cultured in a tissue culture flask in 10% RPMI medium containing 50 μg / mL beta-mercaptoethanol . On the day of phagocytosis, the adhered macrophages were made serum-free in RP MI medium for 2 hours. At the same time, H929 cells were stained with 0.3 μM CFSE dye . After washing, 200,000 CFSE-stained H929 cells were incubated in serum-free medium with anti-human CD47 or mouse IgG1 κ isotype control antibody or various concentrations of test items at 37 °C for 30 minutes. Two hours after serum-free, the macrophages were dissociated with cell dissociation buffer, collected by gentle scraping, and seeded into each well of a ultra-low attachment 96-well plate seeded with H929 cells at a concentration of 50,000 cells per well . Phagocytosis was allowed to proceed for 2 hours. After 2 hours, the cells were washed with PBS and stained in the dark at 4 °C for 30 minutes with 1 μL of anti-human CD11b-APC antibody prepared in 100 μL PBS . The cells were further washed and fixed with 100 μ L solid buffer until captured by flow cytometry. The degree of phagocytosis of H929 cells by human macrophages was measured by capturing the samples by flow cytometry. The samples captured by flow cytometry were analyzed using FlowJo software. Each experimental condition was performed in duplicate. Cells positive for FITC (CFSE) and CD11b-APC were regarded as phagocytosed macrophages. The raw data of the phagocytosis rate % by macrophages were obtained in the form of an Excel sheet from FlowJo. The isotype control The phagocytosis rate % of light (background phagocytosis) was subtracted from the phagocytosis rate % of macrophages treated with the compound and other controls to obtain a corrected phagocytosis value. The corrected phagocytosis value of the sample treated with the compound was calculated using the formula: Normalized phagocytosis rate % = [(Corrected phagocytosis rate % of the compound) / (Corrected phagocytosis rate of B6H1 2)×100] and was normalized to the phagocytosis of the positive control (B6H12).

Table 8

[0234] Example - 4: Efficacy of Compound 6 in A20 Syngeneic Lymphoma Model Female Balb / c (BALB / cAnNTac) mice (6 - 8 weeks old) bred in the facility were used in this efficacy study in the A20 syngeneic lymphoma model. The animals were individually labeled by tail marking and housed in cages identified by cage cards indicating the test code, experimental date, sex, and number of animals. The animals were weighed daily during the experiment. The A20 cell line (a B - cell lymphoma line derived from a spontaneous reticulum cell neoplasm found in aged BALB / cAnN mice) was obtained from ATCC. When the average tumor volume reached approximately 75 mm the animals were randomized into 4 groups of 12 animals each based on tumor volume. Following randomization into the various treatment groups, administration of the vehicle and Compound 6 was initiated. All treatments were administered orally at a dose of 3 mg / kg, 10 mg / Kg, and 30 mg / Kg, twice a day for 21 days. After 21 days of continuous treatment, all efficacy and tolerability were observed for tumors during the treatment period 3 ​​​​​​​​​It was evaluated based on tumor volume and body weight changes. On day 21 of the treatment, animals from all treatment groups were sacrificed in sequence 1 hour after the administration of the final dose.

[0235] The body weight of each individual animal was recorded daily before the administration of the test item throughout the experimental period. The animals were observed once a day throughout the experimental period for mortality / incidence, and also observed once a day throughout the experimental period for clinical signs. Tumor volume was measured three times a week (once every 2 - 3 days) in animals of all treatment groups using a digital caliper. From an ethical perspective, any treatment / control group with an average tumor weight more than 10% of the animal body weight was humanely sacrificed. As a measure of efficacy, %T (treatment) / C (control) and %TGI (% tumor growth inhibition) values were calculated. Graphical and statistical analyses were performed using GraphPad Prism® Version 7.0. In the analysis of tumor volume data, statistical comparisons were performed on day 21 across all groups using one - way ANOVA and Dunnett's multiple comparison test. All analyses and comparisons were evaluated at the 5% (p < 0.05) level. A "p" value less than 0.05 was considered significant . .

[0236] Compound 6 had good tolerance without any signs of weight loss and / or clinical signs of toxicity. Regarding antitumor efficacy, Compound 6 showed statistically significant tumor growth inhibition (TGI) at all tested dose levels. Treatment with Compound 6 resulted in tumor growth inhibition values of 53%, 64% and 67% at doses of 3 mg / kg, 10 mg / kg and 30 mg / kg, respectively. .

Table 9

Claims

1. Formula (I): 【Chemical 1】 (wherein R ａ is hydrogen or acyl; and R １ is hydrogen, -(CH ２ ). ２ CONH ２ , -(CH ２ ). ２ COOH, -CH ２ COOH, -(CH ２ ). ３ NHC(=NH)NH ２ , -(CH ２ ). ４ NH ２ , -CH ２ CONH ２ , -CH(CH ３ ).-CH ２ .-CH ３ , -CH ２ -aryl, or -CH ２ -heteroaryl; said aryl and heteroaryl are unsubstituted; or R ａ and R １ together with the atoms to which they are attached form a pyrrolidine ring optionally substituted with an oxo group; R ２ represents hydrogen, -CH ２ -OH, -(CH ２ ) ３ NH C(=NH)NH ２ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -CH ２ -aryl, or -CH ２ -heteroaryl; said aryl and heteroaryl are unsubstituted; R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -aryl, -(CH ２ ) ３ NH C(=NH)NH ２ -, -CH ２ COOH, -CH(CH ３ )-CH ２ -, -CH ３ -, -CH ２ -CH(CH ３ ) ２ -, -(CH ２ ) ２ CONH ２ -, -(CH ２ ) ２ COOH, -(CH ２ ) ４ NH ２ or -CH ２ -heteroaryl; said aryl and heteroaryl are unsubstituted; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring), or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer, provided that The amide or ester of the compound of formula (I) means a corresponding amide group -C(O)NH ２ or a converter of the carboxyl group to an acid group -C(O)OR11 (R11 is a hydrocarbyl group), the compound of formula (I) is 【Chem.】 a compound that is not, or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer.

2. R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ４ NH ２ , -CH ２ CONH ２ , -CH ２ -aryl, or -CH ２ -heteroaryl; the aryl and heteroaryl being unsubstituted; or R ａ and R １ together with the atom to which they are attached form a pyrrolidine ring; R ２ is hydrogen, -(CH ２ ) ３ NH C(=NH)NH ２ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -CH ２ -aryl, or -CH ２ -heteroaryl; said aryl and heteroaryl being unsubstituted; R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -aryl, -(CH ２ ) ３ NH C(=NH)NH ２ -(CH ２ ) ２ CONH ２ -(CH ２ ) ２ COOH, -(CH ２ ) ４ NH ２ or -CH ２ -heteroaryl; said aryl and heteroaryl being unsubstituted; or R ｂ and R ３ together with the atom to which they are attached form a pyrrolidine ring, the compound according to claim 1.

3. R １ is hydrogen, -(CH ２ ), ２ CONH ２ , -(CH ２ ), ２ COOH, -(CH ２ ), ３ NHC(=NH)NH ２ , -(CH ２ ), ４ NH ２ , -CH ２ CONH ２ , -CH(CH ３ )-CH ２ -CH ３ , -CH ２ -phenyl, -CH ２ -indolyl, or -CH ２ -imidazolyl, and the compound according to claim 1.

4. R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ４ NH ２ , -CH ２ CONH ２ , -CH ２ -phenyl, or -CH ２ -imidazolyl, the compound according to claim 1.

5. R １ is -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ４ NH ２ , -CH ２ CONH ２ , -CH ２ -phenyl, or -CH ２ -imidazolyl, the compound according to claim 1.

6. R ２ is hydrogen, -CH ２ -OH, -(CH ２ ) ３ NH C(=NH)NH ２ -(CH ２ ) ２ CONH ２ -(CH ２ ) ２ COOH, -CH ２ -phenyl, -CH ２ -indolyl or -CH ２ -imidazolyl, and the compound according to any one of claims 1 to 5.

7. R ２ is hydrogen, -(CH ２ ) ３ NH C(=NH)NH ２ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -CH ２ -phenyl, or -CH ２ -imidazolyl, and the compound according to any one of claims 1 to 5.

8. R ２ is hydrogen, -(CH ２ ) ３ NH C(=NH)NH ２ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, or -CH ２ -phenyl, a compound according to any one of claims 1 to 5.

9. R ３ is hydrogen, -(CH ２ ) ３ NH-C(=NH)NH ２ , -CH ２ COOH, -CH(CH ３ )-CH ２ -CH ３ , -CH ２ -CH(CH ３ ) ２ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ４ NH ２ , -CH ２ -phenyl, -CH ２ -indolyl, or -CH ２ -imidazolyl, and the compound according to any one of claims 1 to 8.

10. R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ), ３ NH C(=NH)NH ２ , -(CH ２ ), ２ CONH ２ , -(CH ２ ), ２ COOH, -CH(CH ３ )-CH ２ -CH ３ , -CH ２ -CH(CH ３ ), ２ , -(CH ２ ), ４ NH ２ , or -CH ２ -imidazolyl, and the compound according to any one of claims 1 to 8.

11. R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ３ NH C(=NH)NH ２ -(CH ２ ) ２ CONH ２ -(CH ２ ) ２ COOH, -(CH ２ ) ４ NH ２ or -CH ２ -imidazolyl, and the compound according to any one of claims 1 to 8.

12. R ｂ and R ３ The compound according to claim 1, wherein together with the atoms to which they are attached form a pyrrolidine ring.

13. R ａ is hydrogen or acyl; and R １ is hydrogen, -CH ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ , -CH ２ CONH ２ , -CH(CH ３ )-CH ２ -CH ３ , or -CH ２ -heteroaryl; or R ａ and R １ together with the atoms to which they are attached form a pyrrolidine ring optionally substituted with an oxo group; R ２ represents hydrogen, -CH ２ -OH or -CH ２ -heteroaryl; R ｂ is hydrogen; R ３ is -CH ２ -aryl, -CH ２ COOH, -CH(CH ３ )-CH ２ -CH ３ -CH ２ -CH(CH ３ ) ２ -(CH ２ ) ２ COOH, or -(CH ２ ) ４ NH ２ represents, The compound according to claim 1, represented by the compound of formula (I).

14. R ａ is hydrogen; R １ is -(CH ２ ) ２ CONH ２ ,-(CH ２ ) ４ NH ２ ,-(CH ２ ) ３ NH C(=NH)NH ２ , or -CH ２ -heteroaryl; R ２ is -(CH ２ ) ３ NH C(=NH)NH ２ 、-(CH ２ ) ２ CONH ２ 、-(CH ２ ) ２ COOH, or -CH ２ -aryl; R ｂ is hydrogen; R ３ is hydrogen, -(CH ２ ) ２ CONH ２ , or -CH ２ -heteroaryl; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, The compound according to claim 1, represented by the compound of formula (I).

15. Formula (IA): [Chemical 2] (wherein R １ , R ａ and R ２ are as defined in claim 1), or a pharmaceutically acceptable salt or amide or ester, or stereoisomer thereof, of the compound according to claim 1 represented by the compound.

16. R １ is hydrogen, -CH ２ -COOH, -CH ２ -CONH ２ , -CH(CH ３ ), -CH ２ -CH ３ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ , -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ４ NH ２ , -CH ２ -phenyl, -CH ２ -indolyl or -CH ２ -imidazolyl, the compound according to claim 15.

17. R １ is -(CH ２ ) ２ CONH ２ or -(CH ２ ) ２ COOH, the compound according to claim 15

18. R ２ is hydrogen, -CH ２ -OH, -(CH ２ ) ３ NH C(=NH)NH ２ -(CH ２ ) ２ CONH ２ -(CH ２ ) ２ COOH, -CH ２ -phenyl, or -CH ２ -imidazolyl, and the compound according to claim 15.

19. R ａ is hydrogen; and R １ is hydrogen, -CH ２ -COOH, -CH ２ -CONH ２ , -CH(CH ３ )-CH ２ -CH ３ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ４ NH ２ , -CH ２ -phenyl, -CH ２ -indolyl or -CH ２ -imidazolyl; R ２ is hydrogen, -CH ２ -OH, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ２ COOH, or -CH ２ -phenyl, the compound according to claim 15.

20. Formula (IB): 【Chemical 3】 (wherein R １ , R ａ , R ｂ and R ３ are as defined in claim 1), the compound according to claim 1 represented by the compound, or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer.

21. R １ is hydrogen, -CH ２ -COOH, -CH ２ -CONH ２ , -CH(CH ３ ), -CH ２ -CH ３ , -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ , -(CH ２ ) ４ NH ２ , -CH ２ -indolyl, -CH ２ -imidazolyl or -CH ２ -phenyl, and the compound according to claim 20.

22. R １ is hydrogen, -(CH ２ ), ２ CONH ２ , -(CH ２ ), ２ COOH, -(CH ２ ), ３ NHC(=NH)NH ２ , -(CH ２ ), ４ NH ２ , or -CH ２ -phenyl, the compound according to claim 20.

23. R ｂ is hydrogen; R ３ is hydrogen, -CH ２ -COOH, -CH ２ -CH(CH ３ ) ２ -CH(CH ３ )-CH ２ -CH ３ -(CH ２ ) ４ NH ２ -(CH ２ ) ２ CONH ２ -(CH ２ ) ２ COOH, -CH ２ -phenyl, CH ２ -indolyl or CH ２ -imidazolyl; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, the compound according to claim 20.

24. R １ is hydrogen, -CH ２ -COOH, -CH ２ -CONH ２ , -CH(CH ３ ), -CH ２ -CH ３ , -(CH ２ ), ２ CONH ２ , -(CH ２ ), ２ COOH, -(CH ２ ), ３ NHC(=NH)NH ２ , -(CH ２ ), ４ NH ２ , -CH ２ -indolyl, -CH ２ -imidazolyl or -CH ２ -phenyl; R ｂ is hydrogen; R ３ is hydrogen, -CH ２ -COOH, -CH ２ -CH(CH ３ ) ２ -CH(CH ３ )-CH ２ -CH ３ -(CH ２ ) ４ NH ２ -(CH ２ ) ２ CONH ２ -(CH ２ ) ２ COOH, -CH ２ -phenyl, or CH ２ -imidazolyl; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, the compound according to claim 20.

25. Formula (IC): [Chemical Formula 4] (wherein R １ , R ａ , R ３ and R ｂ are as defined in claim 1), a compound according to claim 1 represented by the compound, or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer.

26. R ａ is hydrogen; R １ is -(CH ２ ) ２ COOH, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ３ NH(C=NH)NH ２ , or -(CH ２ ) ４ NH ２ ; or the compound according to claim 25, wherein Ra and R1 together with the atoms to which they are attached form a pyrrolidine ring.

27. R ｂ is hydrogen; R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ２ CONH ２ or -(CH ２ ) ２ COOH; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, the compound according to claim 25.

28. R ａ is hydrogen; R １ is -(CH ２ ) ２ COOH, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ３ NHC(=NH)NH ２ , or -(CH ２ ) ４ NH ２ ; or R ａ and R １ together with the atoms to which they are attached form a pyrrolidine ring; R ｂ is hydrogen; R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ２ CONH ２ or -(CH ２ ) ２ COOH; or R ｂ and R ３ form a pyrrolidine ring together with the atoms to which they are attached, a compound according to claim 25.

29. Formula (ID): 【Chemical Formula 5】 (wherein R １ , R ａ , R ３ and R ｂ are as defined in claim 1), or a pharmaceutically acceptable salt or amide or ester, or stereoisomer thereof, of the compound according to claim 1, represented by the compound.

30. R １ is -(CH ２ ) ３ NH C(=NH)NH ２ 、-(CH ２ ) ４ NH ２ 、or -C H ２ CONH ２ The compound according to claim 29, which represents

31. R ｂ is hydrogen; R ３ is hydrogen, -(CH ２ ) ３ NH C(=NH)NH ２ or -(CH ２ ) ４ NH ２ ; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, the compound according to claim 29.

32. R １ is -(CH ２ ) ３ NH C(=NH)NH ２ 、-(CH ２ ) ４ NH ２ 、or -CH ２ CONH ２ ; R ｂ is hydrogen; R ３ is hydrogen, -(CH ２ ), ３ NH C(=NH)NH ２ or -(CH ２ ), ４ NH ２ ; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, the compound according to claim 29.

33. Formula (IE): ​ (wherein R ２ , R ３ and R ｂ are as defined in claim 1), the compound according to claim 1 represented by the compound, or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer.

34. R ２ is hydrogen, -CH ２ -OH, -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ 、-CH ２ -phenyl or -CH ２ -indolyl, the compound according to claim 33.

35. R ３ is hydrogen, -CH ２ -COOH, -(CH ２ ) ２ COOH, -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-CH ２ -CH ３ , -(CH ２ ) ４ NH2, -CH ２ -phenyl, -CH ２ -indolyl, or -CH ２ -imidazolyl; or R ｂ and R ３ together with the atom to which they are attached form a pyrrolidine ring, the compound according to claim 33.

36. R ２ is hydrogen, -CH ２ -OH, -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC(=NH)NH ２ 、-CH ２ -phenyl or -CH ２ -indolyl; R ３ is hydrogen, -CH ２ -COOH, -(CH ２ ) ２ COOH, -CH ２ -CH(CH3) ２ , -CH(CH ３ )-CH ２ -CH ３ , -(CH ２ ) ４ NH ２ , -CH ２ -phenyl, -CH ２ -indolyl, or -CH ２ -imidazolyl; or R ｂ and R ３ together with the atom to which they are attached form a pyrrolidine ring, the compound according to claim 33.

37. Formula (IF): [Chemical Formula 7] (wherein R ２ , R ３ and R ｂ are as defined in claim 1), or a pharmaceutically acceptable salt or amide or ester, or stereoisomer thereof, of the compound according to claim 1, represented by the compound.

38. R ２ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ３ NH C(=NH)NH ２ or -(CH ２ ) ２ COOH, and the compound according to claim 37.

39. R ３ is -CH ２ -phenyl, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, or —(CH ２ ) ４ NH ２ The compound according to claim 37, which represents

40. R ２ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ３ NH C(=NH)NH ２ , or -(CH ２ ) ２ COOH; R ３ is -CH ２ -phenyl, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, Or -(CH ２ ) ４ NH ２ The compound according to claim 37, which represents

41. 【Table 1】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt, amide, ester, or stereoisomer thereof, wherein the amide or ester of the compound is a corresponding amide group -C(O)NH ２ Or an acid group -C(O)OR11 (wherein R11 is a hydrocarbyl group), and means a conversion product of a carboxyl group to the above-mentioned compound, or a pharmaceutically acceptable salt, amide, ester, or stereoisomer thereof. An amide and / or ester derivative of the compound represented by

42. , wherein the amide or ester derivative means a carboxyl group converted to a corresponding amide group —C(O)NH ２ or an acid group —C(O)OR11 (R11 is a hydrocarbyl group), and the amide and / or ester derivative.

43. A pharmaceutical composition comprising the compound according to any one of claims 1 to 42 and a pharmaceutically acceptable carrier.

44. A composition for use as a medicament, comprising the compound according to any one of claims 1 to 42.

45. A composition for modulating macrophage phagocytosis activity against cancer cells or tumor cells, comprising the compound according to any one of claims 1 to 42, wherein the cancer cells are melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia including chronic or acute leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) neoplasms, non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, B cell lymphoma, environmentally induced cancers including those induced by asbestos (e.g., mesothelioma), and cells of cancer selected from combinations of said cancers.

46. The composition according to claim 45, wherein the cancer cells are AML cells.

47. A composition for treating or delaying the progression of a CD47-mediated disease or disorder, comprising the compound according to any one of claims 1 to 42.

48. The disease or disorder mediated by CD47 is (i) cancer selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal area, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic or acute leukemia including chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) neoplasms, non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, B cell lymphoma, environmentally induced cancers including those induced by asbestos (e.g., mesothelioma), and combinations of said cancers, or (ii) Pathogenic infections caused by HIV, influenza, herpes, giardia, malaria, leishmania, hepatitis viruses (A, B, & C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis virus, Chlamydia, Rickettsia, Mycobacterium, Staphylococcus, Streptococcus, Neumococcus, meningococcus, and gonococcus, Klebsiella, Proteus, Serratia, Pseudomonas, Escherichia coli, Legionella, diphtheria, Salmonella, Bacillus, cholera, tetanus, botulinum, anthrax, plague, leptospira, and Lyme disease bacteria, pathogenic infections caused by Candida fungi (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Mucorales (Mucor, Absidia, Rhizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum, as well as pathogenic infections caused by Shigella amebic parasites, Balantidium coli, Naegleria fowleri, Acanthamoeba species, Giardia lamblia, Cryptosporidium species, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, or Ancylostoma braziliensis, bacterial infections, viral infections, and fungal infections The composition according to claim 47, which is Claim 49 A composition for treating or delaying the progression of atherosclerosis and multiple sclerosis mediated by CD47, comprising the compound according to any one of claims 1 to 42.

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